Optimization of CAR-T Cell-Based Therapies Using Small-Molecule-Based Safety Switches

Chimeric antigen receptor T cell therapy has demonstrated antileukemia efficacy. However, this therapeutic approach is hampered by severe cytokine release syndrome, which is a major impediment to its widespread application in the clinic. The safety of this approach can be improved by engineering a rapid and reversible "off" or "on" safety switch for CAR-T cells. Cutting-edge investigations combining the advantages of genetic engineering and chemical technology have led to the invention of small-molecule-based safety switches for CAR-T cells. Small molecules such as FITC, folate, rimiducid, rapamycin, proteolysis-targeting chimera (PROTAC) compounds, and dasatinib are being investigated to design such safety switches. Optimized CAR-T cells may have enhanced therapeutic efficiency with fewer adverse effects. Herein we summarize and classify current novel small-molecule-based safety switches for CAR-T cells that aim to provide pharmacological control over the activities and toxicities associated with CAR-T cell-based cancer immunotherapies.